Inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention comprises analogs of the CA 1  A 2  X motif of the protein Ras that is modified by farnesylation in vivo. These CA 1  A 2  X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA 1  A 2  X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A 2  position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

RELATED APPLICATION

The present patent application is a continuation-in-part application ofapplication Ser. No. 08/412,626, filed Mar. 29, 1995, now abandoned.

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a contbrmational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are tbund in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are detective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also famesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci U.S.A.,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However. direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin two general classes. The first are analogs of farnesyl diphosphate(FPP), while the second class of inhibitors is related to the proteinsubstrates (e.g., Ras) for the enzyme. The peptide derived inhibitorsthat have been described are generally cysteine containing moleculesthat are related to the CAAX motif that is the signal for proteinprenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al.,PNAS, 88:732-736 (1991)). Such inhibitors may inhibit proteinprenylation while serving as alternate substrates for thefarnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)). In general, deletion of the thiol from a CAAX derivativehas been shown to dramatically reduce the inhibitory potency of thecompound. However, the thiol group potentially places limitations on thetherapeutic application of FPTase inhibitors with respect topharmacokinetics, pharmacodynamics and toxicity. Therefore, a functionalreplacemen for the thiol is desirable.

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 A1).

It is, therefore. an object of this invention to developtetrapeptide-based compounds that do not have a thiol moiety, and thatwill inhibit farnesyl-protein transferase and thus, thepost-translational farnesylation of proteins. It is a tugher object ofthis invention to develop chemotherapeutic compositions containing thecompounds of this invention and methods for producing the compounds ofthis invention.

SUMMARY OF THE INVENTION

The present invention comprises analogs of the CA¹ A² X motif of theprotein Ras that is modified by farnesylation in vivo. These CA¹ A² Xanalogs inhibit the farnesylprotein transferase. Furthermore, these CA¹A² X analogs differ from those previously described as inhibitors offarnesyl-protein transferase in that they do not have a thiol moiety.The lack of the thiol offers unique advantages in terms of improvedpharmacokinetic behavior in animals, prevention of thiol-dependentchemical reactions, such as rapid autoxidation and disulfide formationwith endogenous thiols, and reduced systemic toxicity. The compounds ofthe instant invention also incorporate a cyclic amine moiety in the A²position of the motif. Further contained in this invention arechemotherapeutic compositions containing these farnesyl transferaseinhibitors and methods for their production.

The compounds of this invention are illustrated by the formulae:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention inhibit the famesyl-protein transferase.In a first embodiment of this invention, the farnesyl-proteintransferase inhibitors are illustrated by the formula I: ##STR2##wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --;

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --.

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR3## R^(4a),R^(4b), R^(7a) and R^(7b) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(5a) and R^(5b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, (R¹⁰)₂ NC(O)--, NO₂,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R^(5a) and R^(5b) are combined to form --(CH₂)_(s) -- wherein one of thecarbon atoms is optionally replaced by a moiety selected from: O,S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

Q is a substituted or unsubstituted nitrogen-containing C₆ -C₉ bicyclicring system, wherein the non-nitrogen containing ring is selected froman aromatic ring and a heterocycle;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention the prodrugs of compounds offormula I are illustrated by the formula II: ##STR4## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR5## R^(4a),R^(4b), R^(7a) and R^(7b) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(5a) and R^(5b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, (R¹⁰)₂ NC(O)-, NO₂,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ OC(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OCO(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R^(5a) and R^(5b) are combined to form --(CH₂)_(s) -- wherein one of thecarbon atoms is optionally replaced by a moiety selected from: O,S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m), R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OCO(O)NR¹⁰ 13 , and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is

a) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine, wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from:

1) C₁ -C₆ alkyl,

2) aryl,

3) heterocycle,

4) --N(R¹¹)₂,

5) --OR¹⁰, or

b) ##STR6## R¹³ is independently selected from hydrogen and C₁ -C₆alkyl;

R¹⁴ is independently selected from C₁ -C₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

Q is a substituted or unsubstituted nitrogen-containing C₆ -C₉ bicyclicring system, wherein the non-nitrogen containing ring is selected froman aromatic ring and a heterocycle;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors of farnesyltransferase are illustrated by the formula III: ##STR7## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR8## R^(4a),R^(4b), R^(7a) and R^(7b) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

Q is a substituted or unsubstituted nitrogen-containing C₆ -C₉ bicyclicring system, wherein the non-nitrogen containing ring is selected froman aromatic ring and a heterocycle;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

the pharmaceutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of compounds offormula III are illustrated by the formula IV: ##STR9## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)--NR¹⁰ --;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR10## R^(4a),R^(4b), R^(7a) and R^(7b) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m), R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

Q is a substituted or unsubstituted nitrogen-containing C₆ -C₉ bicyclicring system, wherein the non-nitrogen containing ring is selected froman aromatic ring and a heterocycle;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the Ras farnesyltransferase inhibitors are illustrated by the Formula I: ##STR11##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR12## R^(4a)and R^(7a) are independently selected from: a) hydrogen,

b) C₁ -C ₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ C₁₀ cycloalkyl;

R^(4b) and R^(7b) are hydrogen;

R^(5a) is selected from:

a) a side chain of a naturally occurring amino acid, wherein the aminoacid is selected from methionine and glutamine,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R^(5b) is selected from:

a) hydrogen, and

b) C₁ -C₃ alkyl;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

Q is selected from: ##STR13## A¹ and A² are independently selected from:a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--,or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected front pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the prodrugs ofthe preferred compounds of Formula I are illustrated by the Formula II:##STR14## wherein: R^(1a) is independently selected from: hydrogen or C₁-C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfox ide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR15## R^(4a)and R^(7a) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(4b) and R^(7b) are hydrogen;

R^(5a) is selected from:

a) a side chain of a naturally occurring amino acid, wherein the aminoacid is selected from methionine and glutamine,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R^(5b) is selected from:

a) hydrogen, and

b) C₁ -C₃ alkyl;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m), R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is

a) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine, wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from:

1) C₁ -C₆ alkyl,

2) aryl,

3) heterocycle,

4) --N(R¹¹)₂,

5) --OR¹⁰, or

b) ##STR16## R¹³ is independently selected from hydrogen and C₁ -C₆alkyl;

R¹⁴ is independently selected from C₁ -C₆ alkyl;

Q is selected from: ##STR17## A¹ and A² are independently selected from:a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--,or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a third more preferred embodiment of this invention, the inhibitorsof farnesyl transferase are illustrated by the formula III: ##STR18##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR19## R^(4a)and R^(7a) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m), R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(4b) and R^(7b) are hydrogen;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected frown C₁ -C₆ alkyl and aryl;

Q is selected from: ##STR20## A¹ and A² are independently selected from:a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--,or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a fourth more preferred embodiment of this invention, the prodrugs ofthe preferred compounds of Formula III are illustrated by the FormulaIV: ##STR21## wherein: R^(1a) is independently selected from: hydrogenor C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R² and R³ are combined to form --(CH₂)_(s) --; or

R² or R³ are combined with R⁶ to form a ring such that ##STR22## R^(4a)and R^(7a) are independently selected from: a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(4b) and R^(7b) are hydrogen;

R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

Q is selected from: ##STR23## A¹ and A² are independently selected from:a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--,or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

X, Y and Z are independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

N-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

N-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

N-[(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionine methyl ester

N-[(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonylmethionine

N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

N-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

or the pharmaceutically acceptable salts or optical isomer thereof.

Specific examples of compounds of the invention are:

N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine##STR24##N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester ##STR25## or the pharmaceutically acceptable salts oroptical isomer thereof.

In the present invention, the amino acids which are disclosed areidentified both by conventional 3 letter and single letter abbreviationsas indicated below:

    ______________________________________                                        Alanine            Ala        A                                               Arginine           Arg        R                                               Asparagine         Asn        N                                               Aspartic acid      Asp        D                                               Asparagine or      Asx        B                                               Aspartic acid                                                                 Cysteine           Cys        C                                               Glutamine          Gln        Q                                               Glutamic acid      Glu        E                                               Glutamine or       Glx        Z                                               Glutamic acid                                                                 Glycine            Gly        G                                               Histidine          His        H                                               Isoleucine         Ile        I                                               Leucine            Leu        L                                               Lysine             Lys        K                                               Methionine         Met        M                                               Phenylalanine      Phe        F                                               Proline            Pro        P                                               Serine             Ser        S                                               Threonine          Thr        T                                               Tryptophan         Trp        W                                               Tyrosine           Tyr        Y                                               Valine             Val        V                                               ______________________________________                                    

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

As used herein, "aryl" is intended to include any stable monocyclic,bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring,wherein at least one ring is aromatic. Examples of aryl groups includephenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl,phenanthrenyl and the like.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicor stable 11-15 membered tricyclic heterocycle ring which is eithersaturated or unsaturated, and which consists of carbon atoms and fromone to four heteroatoms selected from the group consisting of N, O, andS, and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. Examples of such heterocyclic elementsinclude, but are not limited to, azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl,imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide,pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.

As used herein, the terms "substituted aryl", "substituted heterocycle"and "substituted cycloalkyl" are intended to include the cyclic groupwhich is substituted with 1 or 2 substitutents selected from the groupwhich includes but is not limited to F, Cl, Br, CF₃, NH₂, N(C₁ -C₆alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--, --OH, (C₁ -C₆ alkyl)S(O)_(m) --,(C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--, (C₁ -C₆ alkyl)C(O)--, (C₁ -C₆alkyl)OC(O)--, N₃, (C₁ -C₆ alkyl)OC(O)NH-- and C₁ -C₂₀ alkyl.

The following structure: ##STR26## represents a cyclic amine moietyhaving 5 or 6 members in the ring, such a cyclic amine which may beoptionally fused to a phenyl or cyclohexyl ring. Examples of such acyclic amine moiety include, but are not limited to, the followingspecific structures: ##STR27## It is also understood that substitutionon the cyclic amine moiety by R^(8a) and R^(8b) may be on differentcarbon atoms or on the same carbon atom.

When R³ and R⁴ are combined to form --(CH₂)_(s) --, cyclic moieties areformed. Examples of such cyclic moieties include, but are not limitedto: ##STR28##

When R^(5a) and R^(5b) are combined to form --(CH₂)_(s) --, cyclicmoieties as described hereinabove for R³ and R⁴ are formed. In addition,such cyclic moieties may optionally include a heteroatom(s). Examples ofsuch heteroatom-containing cyclic moieties include, but are not limitedto: ##STR29##

As used herein, the phrase "nitrogen containing C₆ -C₉ bicyclic ringsystem wherein the non-nitrogen containing ring is selected from anaromatic ring and a heterocycle" which defines moiety "Q" of the instantinvention includes but is not limited to the following ring systems:##STR30##

It is well understood by persons of ordinary skill in the art that the"side chain" of the naturally occurring amino acid glycine is a hydrogenmoiety.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable (e.g.,R¹⁰, Z, n, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. Thus, --N(R¹⁰)₂represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understood thatsubstituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to providecompounds that are chemically stable and that can be readily synthesizedby techniques known in the art as well as those methods set forth below.

Preferably, R^(1a) and R^(1b) are independently selected from: hydrogen,--N(R⁸)₂, R⁸ C(O)NR⁸ -- or C₁ -C₆ alkyl unsubstituted or substituted by--N(R⁸)₂, R⁸ O-- or R⁸ C(O)NR⁸ --. Preferably, R² is the sidechain ofglycine (hydrogen). Preferably, R³ is selected from:

a) a side chain of a naturally occurring amino acid,

b) substituted or unsubstituted C₁ -C₂₀ alkyl,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

c) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ C₁₀ cycloalkyl; or

R³ is combined with R⁶ to form pyrrolidinyl ring.

Preferably, R^(4a), R^(4b), R^(7a) and R^(7b) are independently selectedfrom: hydrogen, C₁ -C₆ alkyl, aryl and benzyl.

Preferably, R^(5a) and R^(5b) are independently selected from:

a side chain of a naturally occurring amino acid, methionine sulfoxide,methionine sulfone and unsubstituted or substituted C₁ -C₆ alkyl.

Preferably, R⁶ is: hydrogen or is combined with R³ to form pyrrolidinylring.

Preferably, R⁸ is selected from: hydrogen, perfluoroalkyl, F, Cl, Br,R¹⁰ O--, R¹¹ S(O)_(m) --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ -- and C₁ -C₆ alkyl.

Preferably, R⁹ is hydrogen.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, R¹² is selected from C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, Q is a tetrahydroisoquinolinyl moiety.

Preferably, V is selected from hydrogen, heterocycle and aryl.

Preferably, n, p and r are independently 0, 1, or 2.

Preferably t is 3.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety conventional chemical methods. Generally, the salts areprepared by ion exchange chromatography or by reacting the free basewith stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

The compounds of the invention can be synthesized from their constituentamino acids by conventional peptide synthesis techniques, and theadditional methods described below. Standard methods of peptidesynthesis are disclosed, for example, in the following works: Schroederet al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky etal., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.)"Protective Groups in Organic Chemistry", Plenum Press, 1973, or Baranyet al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1,Academic Press, 1980, or Stewart et al., "Solid Phase PeptideSynthesis", Second Edition, Pierce Chemical Company, 1984. The teachingsof these works are hereby incorporated by reference.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

Ac₂ O Acetic anhydride;

Boc t-Butoxycarbonyl;

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene;

DMAP 4-Dimethylaminopyridine;

DME 1,2-Dimethoxyethane;

DMF Dimethylformamide;

EDC₁ -(3-dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride;

HOBT 1-Hydroxybenzotriazole hydrate;

Et₃ N Triethylamine;

EtOAc Ethyl acetate;

FAB Fast atom bombardment;

HOOBT 3-Hydroxy- 1,2,2-benzotriazin-4(3H)-one;

HPLC High-performance liquid chromatography;

MCPBA m-Chloroperoxybenzoic acid;

MsCl Methanesulfonyl chloride;

NaHMDS Sodium bis(trimethylsilyl)amide;

Py Pyridine;

TFA Trifluoroacetic acid;

THF Tetrahydrofuran.

Compounds of this invention are prepared by employing the reactionsshown in the tollowing Reaction Schemes A-J, in addition to otherstandard manipulations such as ester hydrolysis, cleavage of protectinggroups, etc., as may be known in the literature or exemplified in theexperimental procedures. Some key bond-forming and peptide modifyingreactions are:

Reaction A Amide bond formation and protecting group cleavage usingstandard solution or solid phase methodologies.

Reaction B Preparation of a reduced peptide subunit by reductivealkylation of an amine by an aldehyde using sodium cyanoborohydride orother reducing agents.

Reaction C Deprotection of the reduced peptide subunit

Reaction D Peptide bond formation and protecting group cleavage usingstandard solution or solid phase methodologies.

Reaction E Preparation of a reduced subunit by borane reduction of theamide moiety.

Reaction Schemes A-E illustrate bond-forming and peptide modifyingreactions incorporating acyclic peptide units. It is well understoodthat such reactions are equally useful when the --NHC(R^(A))-- moiety ofthe reagents and compounds illustrated is replaced with the followingmoiety: ##STR31## These reactions may be employed in a linear sequenceto provide the compounds of the invention or they may be used tosynthesize fragments which are subsequently joined by the reactionsdescribed in the Reaction Schemes. ##STR32## where R^(A) is R², R³,R^(5a) or R^(5b) as previously defined; R^(4a) and R.sup. 4b are aspreviously defined; and R is an appropriate protecting group for thecarboxylic acid.

Reaction Schemes F-M illustrate reactions wherein thenon-sulfhydryl-containing moiety at the N-terminus of the compounds ofthe instant invention is attached to an acyclic peptide unit which maybe further elaborated to provide the instant compounds. It is wellunderstood that such reactions are equally useful when the--NHC(R^(A))-- moiety of the reagents and compounds illustrated isreplaced with the following moiety: ##STR33## These reactions may beemployed in a linear sequence to provide the compounds of the inventionor they may be used to synthesize fragments which are subsequentlyjoined by the reactions described in Reaction Schemes A-E.

The intermediates whose synthesis are illustrated in Reaction Schemes Aand C can be reductively alkylated with a variety of aldehydes, such asI, as shown in Reaction Scheme F. The aldehydes can be prepared bystandard procedures, such as that described by O. P. Goel, U. Krolls, M.Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from theappropriate amino acid (Reaction Scheme F). The reductive alkylation canbe accomplished at pH 5-7 with a variety of reducing agents, such assodium triacetoxyborohydride or sodium cyanoborohydride in a solventsuch as dichloroethane, methanol or dimethylformamide. The product IIcan be deprotected to give the final compounds III with trifluoroaceticacid in methylene chloride. The final product III is isolated in thesalt form, for example, as a trifluoroacetate, hydrochloride or acetatesalt, among others. The product diamine III can further be selectivelyprotected to obtain IV, which can subsequently be reductively alkylatedwith a second aidehyde to obtain V. Removal of the protecting group, andconversion to cyclized products such as the dihydroimidazole VII can beaccomplished by literature procedures.

Alternatively, the protected dipeptidyl analog intermediate can bereductively alkylated with other aldehydes such as1-trityl-4-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to giveproducts such as VIII (Reaction Scheme G). The trityl protecting groupcan be removed from VIII to give IX, or alternatively, VIII can first betreated with an alkyl halide then subsequently deprotected to give thealkylated imidazole X. Alternatively, the dipeptidyl analog intermediatecan be acylated or sulfonylated by standard techniques.

The imidazole acetic acid XI can be converted to the acetate XIII bystandard procedures, and XIII can be first reacted with an alkyl halide,then treated with refluxing methanol to provide the regiospecificallyalkylated imidazole acetic acid ester XIV. Hydrolysis and reaction withthe protected dipeptidyl analog intermediate in the presence ofcondensing reagents such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylatedproducts such as XV.

If the protected dipeptidyl analog intermediate is reductively alkylatedwith an aldehyde which also has a protected hydroxyl group, such as XVIin Reaction Scheme I, the protecting groups can be subsequently removedto unmask the hydroxyl group (Reaction Schemes I, J). The alcohol can beoxidized under standard conditions to e.g. an aidehyde, which can thenbe reacted with a variety of organometallic reagents such as Grignardreagents, to obtain secondary alcohols such as XX. In addition, thefully deprotected amino alcohol XXI can be reductively alkylated (underconditions described previously) with a variety of aldehydes to obtainsecondary amines, such as XXII (Reaction Scheme K), or tertiary amines.

The Boc protected amino alcohol XVIII can also be utilized to synthesize2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme L).Treating XVIII with 1,1'-sulfonyldiimidazole and sodium hydride in asolvent such as dimethylformamide led to the formation of aziridineXXIII. The aziridine reacted in the presence of a nucleophile, such as athiol, in the presence of base to yield the ring-opened product XXIV.

In addition, the protected dipeptidyl analog intermediate can be reactedwith aldehydes derived from amino acids such as O-alkylated tyrosines,according to standard procedures, to obtain compounds such as XXX, asshown in Reaction Scheme M. When R' is an aryl group, XXX can first behydrogenated to unmask the phenol, and the amine group deprotected withacid to produce XXXI. Alternatively, the amine protecting group in XXXcan be removed, and O-alkylated phenolic amines such as XXXII produced.

Similar procedures as are illustrated in Reaction Schemes F-M may beemployed using other peptidyl analog intermediates such as those whosesynthesis is illustrated in Reaction Schemes B-E.

Reaction Schemes N-R illustrate syntheses of suitably substitutedaldehydes useful in the syntheses of the instant compounds wherein thevariable W is present as a pyridyl moiety. Similar synthetic strategiesfor preparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art. ##STR34##

The instant compounds are useful as pharmaceutical agents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas formation (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) orby other mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine.1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal,2:A3160 (1988)).

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's intramuscular blood-stream by local bolusinjection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 20mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 10 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offamesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be usetill in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

The standard workup referred to in the examples refers to solventextraction and washing the organic solution with 10% citric acid, 10%sodium bicarbonate and brine as appropriate. Solutions were dried oversodium sulfate and evaporated in vacuo on a rotary evaporator.

EXAMPLE 1

Preparation ofN-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester and

N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninetrifluoroacetate

Step A: N-(t-Butoxycarbonyl)-isoleucinal

This compound was synthesized by applying the procedure of Goel, Krolls,Slier, and Kesten [Organic Syntheses, 67, 69 (1988)] toN-(t-butoxycarbonyl-isoleucine. The compound was obtained as a colorlessoil, which was used without purification.

Step B:N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylicacid benzyl ester.

N-(t-Butyloxycarbonyl)-isoleucinal (1.5 g, 0.0070 mol) and1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester (2.23g, 0.0084 mol) were dissolved in MeOH (30 mL) at ambient temperatureunder nitrogen and treated with 3A molecular sieves (3 g) and sodiumcyanoborohydride (0.66 g, 0.0105 mol) with stirring. After 18 h themixture was filtered, concentrated, and the residue was partitionedbetween EtOAc (50 mL) and said aq NaHCO₃ solution (50 mL). The basiclayer was washed with EtOAc (3×30 mL), the organics combined, washedwith brine, and dried (Na₂ SO₄). Filtration and concentration to drynessgave the title compound as a colorless oil after chromatography (SiO₂,hexane: EtOAc, 6:1). ¹ H NMR (CDCl₃) δ 7.02-7.35 (m, 9H), 5.11 (s, 2H),4.6-4.78 (m, 1H), 3.98 (s, 2H), 3.84 (t, 1H, J=5 Hz), 3.64-3.75 (m, 1H),3.05-3.27 (m, 2H), 2.84 (dd, 1H, J=5, 13 Hz), 2.59 (dd, 1H, J=5, 13 Hz),1.70-1.82 (m, 1H), 1.40 (s, 9H), 1.26-1.37 (m, 1H), 0.97-1.13 (m, 1H),0.92 (d, 3H, J=7 Hz), 0.86 (t, 3H, J=7 Hz).

Step C:N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S),isoquinolinecarboxylic acid

N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylicacid benzyl ester (1.5 g, 0.0032 mol) was dissolved in methanol (50mL)--EtOAc (50 mL), treated with 10% palladium on carbon (0.15 g) andhydrogenated under a balloon of hydrogen for 4 h. Filtration andconcentration to dryness gave the title compound as a white solid whichwas used without further purification.

Step D:N-[2(S)-(t-Butyloxycarbonylamino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylicacid (0.67 g, 0.00178 mol) was dissolved in DMF (10 mL) with stirring atambient temperature and treated with EDC (0.376 g, 0.00196 mol), HOBT(0.265 g, 0.00196 mol), and methionine methyl ester hydrochloride (0.427g, 0.00214 mol). The pH was adjusted to 7 with Et₃ N (0.546 mL, 0.00392mol) and stirring was continued for 18 h. The reaction mixture wasconcentrated, then partitioned between EtOAc (50 mL)--H₂ O (50 mL). Theaq layer was washed with EtOAc (2×30 mL), the organics combined, washedwith aq said NaHCO₃ solution, brine, and dried (Na₂ SO₄). Filtration andconcentration gave the title compound alter chromatography (SiO₂, CH₂Cl₂ : MeOH, 99.5:0.5). ¹ H NMR (CD₃ OD) δ 7.05-7.2 (m, 4H), 4.43-4.52(m, 1H), 3.98 (d, 1H, J=13 Hz), 3.68-3.82 (m, 2H), 4.87 (s, 3H), 3.55(t, 1H, J=6 Hz), 2.96-3.14 (m, 2H), 2.84 (dd, 1H, J=5, 13 Hz), 2.70 (dd,1H, J=5,13 Hz), 1.88-2.14 (m, 2H), 1.95 (s, 3H), 1.32-1.57(m, 2H), 1.41(s, 9H), 1.06-1.25 (m, 1H), 0.84-0.96 (m, 6H).

Step E:N-[2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

HCl gas was bubbled into a solution ofN-[2(S)-(t-butyloxycarbonylamino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester (0.37 g, 0.71 mmol) in EtOAc (25 mL) with stirring at -20°C. over 0.5 h. The solution was purged with argon for 0.5 h, thenconcentrated to give the title compound as a white solid which was usedwithout further purification.

Step F:N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester trifluoroacetate

1H-Imidazol-4-ylacetic acid (0.18 g, 1.11 mmol) was dissolved in DMF (10mL) and treated with EDC (0.213 g, 1.11 mmol), HOBT (0.15 g, 1.11 mmol),andN-[2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester (0.275 g, 0.556 mmol) with stirring at ambient temperature.Et₃ N (0.618 mL, 4.44 mol) was added to bring the pH of the solution to8, and stirring was continued for 16 h. The reaction mixture wasconcentrated to remove the DMF, and the residue was partitioned betweenEtOAc (20 mL) and H₂ O (30 mL). The aqueous layer was washed with EtOAc(3×20 mL), the organics combined, washed with brine and dried (Na₂ SO₄).Filtration and concentration to dryness gave the title compound afterpreparative reverse phase chromatography (CH₃ CN: H₂ O gradient). ¹ HNMR (CD₃ OD) δ 8.48 (s, 1H), 7.07 (s, 1H), 6.92-7.04 (m, 4H), 4.29 (d,1H, J=14 Hz), 4.0-4.15 (m, 3H), 3.85-3.9 (m, 1H), 3.45 (ABq, 2H), 3.35(s, 3H), 2.9-3.2 (m, 4H), 2.05-2.2 (m, 2H), 1.72 (s, 3H), 1.55-1.7 (m,2H), 1.2-1.35 (m, 1H), 1.1-1.20 (m, 1H), 0.8-0.9 (m, 1H), 0.55-0.6 (m,6H). FAB MS 530 (M+1).

Step G:N-[(1H-imidazol-4-ylacetyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninetrifluoroacetate

N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester (0.037 g, 0.049 mmol) was dissolved in CH₃ OH (2 mL) in anice-H₂ O bath and treated with 1n NaOH (0.195 mL, 0.195 mmol) withstirring. After 3 h the reaction mixture was neutralized with 1N HCl(0.195 mL, 0.195 mmol), then chromatographed on a preparative VYDACreverse phase column, eluting with 0.1% TFA, H₂ O: 0.1% TFA, CH₃ CN 95:5to 5:95 gradient to give the title compound. ¹ H NMR (CD₃ OD) δ 8.81 (s,1H), 7.42 (s, 1H), 7.2-7.4 (m, 4H), 4.52 (d, 1H, J=14 Hz), 4.25-4.45 (m,3H), 4.15-4.25 (m, 1H), 3.80 (ABq, 2H), 3.25-3.5 (m, 2H), 2.3-2.5 (m,2H), 2.05 (s, 3H), 2.03-2.15 (m, 1H), 1.9-2.0 (m, 1H), 1.57-1.7 (m, 1H),1.42-1.55 (m, 1H), 1.1-1.23 (m, 1H), 0.9-1.0 (m, 6H). FAB MS 516 (M+1).

Using the methods outlined above, the following compounds are prepared:

N-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)- methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methylester

N-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

EXAMPLE 2

Preparation ofN-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionine methyl ester and

N-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionine

Step A: 1H-Imidazole-4-acetic acid methyl ester hydrochloride

A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00 g, 24.6mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride.The resulting solution was allowed to stand at room temperature (RT) for18 hr. The solvent was evaporated in vacuo to afford the title compoundas a white solid.

¹ H NMR(CDCl₃, 400 MHz) δ 8.85(1H, s),7.45(1H, s), 3.89(2H, s) and3.75(3H, s) ppm.

Step B: 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester

To a solution of 1H-imidazole-4-acetic acid methyl ester hydrochloride(24.85 g, 0.141 mol) in dimethyl formamide (DMF) (115 ml) was addedtriethylamine (57.2 ml, 0.412 mol) and triphenylmethyl bromide(55.3 g,0.171 mol) and the suspension was stirred for 24 hr. After this time,the reaction mixture was diluted with ethyl acetate (EtOAc) (1 l) andwater (350 ml). The organic phase was washed with sat. aq. NaHCO₃ (350ml), dried (Na₂ SO₄) and evaporated in vacuo. The residue was purifiedby flash chromatography (SiO₂, 0-100% ethyl acetate in hexanes; gradientelution) to provide the title compound as a white solid.

¹ H NMR (CDCl₃, 400 MHz) δ 7.35(1H, s), 7.31(9H, m), 7.22(6H, m),6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.

Step C: [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester

To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methylester (8.00 g, 20.9 mmol) in acetonitrile (70 ml) was addedbromo-p-toluonitrile (4.10 g, 20.92 mmol) and heated at 55° C. for 3 hr.After this time, the reaction was cooled to room temperature and theresulting imidazolium salt (white precipitate) was collected byfiltration. The flitrate was heated at 55° C. for 18 hr. The reactionmixture was cooled to room temperature and evaporated in vacuo. To theresidue was added EtOAc (70 ml) and the resulting white precipitatecollected by filtration. The precipitated imidazolium salts werecombined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resultingresidue was suspended in EtOAc (75 ml) and the solid isolated byfiltration and washed (EtOAc). The solid was treated with sat aq NaHCO₃(300 ml) and CH₂ Cl₂ (300 ml) and stirred at room temperature for 2 hr.The organic layer was separated, dried (MgSO₄) and evaporated in vacuoto afford the title compound as a white solid:

¹ HNMR(CDCl₃, 400 MHz) δ 7.65(1H, d, J=8Hz), 7.53(1H, s), 7.15(1H, d,J=8 Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid

A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methylester (4.44 g, 17.4 mmol ) in THF (100 ml) and 1M lithium hydroxide(17.4 ml, 17.4 mmol) was stirred at RT for 18 hr. 1M HCl (17.4 ml) wasadded and the THF was removed by evaporation in vacuo. The aqueoussolution was lyophilized to afford the title compound containing lithiumchloride as a white solid.

¹ H NMR(CD₃ OD, 400 MHz) δ 8.22(1H, s), 7.74(1H, d, J=8.4 Hz), 7.36(1H,d, J=8.4 Hz), 7.15(1H, s), 5.43(2H, s) and 3.49(2H, s) ppm.

Step C: [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester

To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methylester (8.00 g, 20.9 mmol) in acetonitrile (70 ml) was addedbromo-p-toluonitrile (4.10 g, 20.92 mmol) and heated at 55° C. for 3 hr.After this time, the reaction was cooled to room temperature and theresulting imidazolium salt (white precipitate) was collected byfiltration. The filtrate was heated at 55° C. for 18 hr. The reactionmixture was cooled to room temperature and evaporated in vacuo. To theresidue was added EtOAc (70 ml) and the resulting white precipitatecollected by filtration. The precipitated imidazolium salts werecombined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resultingresidue was suspended in EtOAc (75 ml) and the solid isolated byfiltration and washed (EtOAc). The solid was treated with sat aq NaHCO₃(300 ml) and CH₂ Cl₂ (300 ml) and stirred at room temperature for 2 hr.The organic layer was separated, dried (MgSO₄) and evaporated in vacuoto afford the title compound as a white solid:

¹ HNMR(CDCl₃, 400 MHz) δ 7.65(1H, d, J=8 Hz), 7.53(1H, s), 7.15(1H, d,J=8 Hz), 7.04(1H, s), 5.24(2H, s), 3.62(3H, s) and 3.45(2H, s) ppm.

Step D: [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid

A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methylester (4.44 g, 17.4 mmol) in THF (100 ml) and 1M lithium hydroxide (17.4ml, 17.4 mmol) was stirred at RT for 18 hr. 1M HCl (17.4 ml) was addedand the THF was removed by evaporation in vacuo. The aqueous solutionwas lyophilized to afford the title compound containing lithium chlorideas a white solid.

¹ H NMR(CD₃ OD, 400 MHz) δ 8.22(1H, s), 7.74(1H, d, J=8.4 Hz), 7.36(1H,d, J=8.4 Hz), 7.15(1H, s), 5.43(2H, s) and 3.49(2H, s) ppm.

Step E:N-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionine methyl ester

Using the method described in Example 1, Step F, but substituting[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid for1H-imidazol-4-ylacetic acid, the title compound is obtained.

Step F: N-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionine

Using the method described in Example 1, Step G, the title compound isobtained.

EXAMPLE 3

Prearation ofN-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninetrifluoroacetate

Step A:N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester trifiuoroacetate

Following the methods described in Example 1, but using L-pyroglutamicacid in place of 1H-imidazol-4-yl acetic acid, the title compound wasprepared. Anal. calcd for C₂₇ H₄₀ N₄ O₅ S.1.5 CF₃ CO₂ H: C, 51.20; H,5.94; N, 7.96; Found: C, 51.01; H, 6.00; N, 8.23.

Step B:N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninetrifluoroacetate

The title compound was prepared following the method dscribed in Example1, Step G. FAB MS 519 (M+1).

EXAMPLE 4

Preparation ofN-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester and

N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

Step A: L-Pyroglutamic acid methyl ester

L-Pyroglutamic acid (15.17 g, 0.1175 mol) was dissolved in CH₃ OH (100mL), cooled to 0° C. under Ar and treated dropwise with thionyl chloride(18.9 mL, 0.259 mol) with stirring. The bath was removed and stirringwas continued at ambient temperature for 3.5 h. Water (150 mL) and solidNaHCO₃ (60 g) were added, the CH₃ OH was removed on a rotary evaporator,and the residue extracted with CH₂ Cl₂ (3×150 mL). The organic layerswere combined, washed with brine, dried (MgSO₄), filtered andconcentrated to dryness to give the title compound.

Step B: N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester

L-Pyroglutamic acid methyl ester (1.36 g, 0.0095 mol) was dissolved indry THF (20 mL) under Ar, treated with NaH (60% oil dispersion) (0.58 g,0.0145 mol) with stirring for 5 min, then the mixture was cooled to 0°C. p-Cyanobenzylbromide (1.78 g, 0.0091 mol) was added, and the mixtureleft to slowly warm to ambient temperature. After 48 h the reactionmixture was partitioned between EtOAc and satd NaHCO₃ solution, theaqueous layer separated and washed with CH₂ Cl₂, the organics combined,washed with brine and dried (MgSO₄). Filtration and concentration todryness followed by trituration with ether gave the white solid product.¹ H NMR(CDCl₃, 400 MHz) δ 7.62(2H, d, J=8 Hz), 7.33(2H, d, J=8 Hz),4.98(1H, d, J=15.4 Hz), 4.13(1H, d, J=15.4 Hz), 3.99(1H, dd, J=3, 9 Hz)and 2.5-2.6 (1H, m), 2.4-2.5 (1H, m), 2.2-2.45 (1H, m), 2.1-2.2 (1H, m)ppm.

Step C: N-(4-Cyanobenzyl)-L-pyroglutamic acid

N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester (0.875 g, 0.0034 mol)was dissolved in THF:H₂ O (3:1) (12 mL) and treated with LiOH (0.294 g,0.007 mol) with stirring at ambient temperature. After stirring for 3 h,the solution was neutralized with 1N HCl, and concentrated to dryness togive the title compound and 2.1 eq of LiCl which was used withoutfurther purification.

Step D:N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester

Using the method described in Example 1, Step F, but substitutingN-(4-Cyanobenzyl)-L-pyroglutamic acid for 1H-imidazol-4-ylacetic acid,the title compound is obtained.

Step E:N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine

Using the method described in Example 1, Step G, the title compound isobtained.

EXAMPLE 5 In Vitro Inhibition of Ras Farnesyl Transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM [³ H]-farnesyl diphosphate ([³ H]-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvestor. washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the [³ H]-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993 ). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention described in Examples 1. Step G,and Example 3, Step B, were tested for inhibitory activity against humanFPTase by the assay described above and were found to have IC₅₀ of <10μM.

EXAMPLE 6 In vivo Ras Farnesylation Assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or N1H3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supple-meted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi[³⁵ S]methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTF) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates axewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

EXAMPLE 7 In Vivo Growth Inhibition Assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits Rasfarnesyl-transferase having the Formula I: ##STR35## wherein: R^(1a) andR^(1b) are independently selected from:a) hydrogen, b) aryl,heterocycle, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR ¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --; R² and R³ areindependently selected from:a) a side chain of a naturally occurringamino acid, b) an oxidized form of a side chain of a naturally occurringamino acid which is:i) methionine sulfoxide, or ii) methionine sulfone,and c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃-C₁₀ cycloalkyl, aryl or heterocyclic group,wherein the substituent isselected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R² and R³ are combined toform --(CH₂)_(s) --; or R² or R³ are combined with R⁶ to form a ringsuch that ##STR36## R^(4a), R^(4b), R^(7a) and R^(7b) are independentlyselected from: a) hydrogen,b) C₁ -C₆ alkyl unsubstituted or substitutedby alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c)caryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R^(5a) and R^(5b) are independently selected from:a)a side chain of a naturally occurring amino acid, b) an oxidized form ofa side chain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C₁-C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclegroup,wherein the substituent is selected from F, Cl, Br, (R¹⁰)₂NC(O)--, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, d) C₁ -C₆ alkyl substituted with an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; or R^(5a) and R^(5b) are combined to form --(CH₂)_(s) --wherein one of the carbon atoms is optionally replaced by a moietyselected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--; R⁶ isindependently selected from hydrogen or C₁ -C₆ alkyl; R⁸ isindependently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl,alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ; Q is a substituted orunsubstituted nitrogen-containing C₆ -C₉ bicyclic ring system, whereinthe non-nitrogen containing ring is selected from an aromatic ring and aheterocycle; V is selected from:a) hydrogen, b) heterocycle, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,providedthat V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ isa bond, n is 0 and A² is S(O)_(m) ; W is a heterocycle; X, Y and Z areindependently H₂ or O;m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4or 5; t is 3, 4 or 5; and u is 0 or 1;or a pharmaceutically acceptablesalt thereof.
 2. A prodrug of the compound according to claim 1illustrated by the formula II: ##STR37## wherein: R^(1a) and R^(1b) areindependently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocyclic, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --; R² and R³ are independently selectedfrom:a) a side chain of a naturally occurring amino acid, b) an oxidizedform of a side chain of a naturally occurring amino acid which is:i)methionine sulfoxide, or ii) methionine sulfone, and c) substituted orunsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group,wherein the substituent is selected from F, Cl,Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with an unsubstitutedor substituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; or R² and R³ are combined to form --(CH₂)_(s) --; or R² orR³ are combined with R⁶ to form a ring such that ##STR38## R^(4a),R^(4b), R^(7a) and R^(7b) are independently selected from: a)hydrogen,b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) aryl,heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R^(5a) and R^(5b) are independently selected from:a)a side chain of a naturally occurring amino acid, b) an oxidized form ofa side chain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C₁-C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclegroup,wherein the substituent is selected from F, Cl, Br, (R¹⁰)₂NC(O)--, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, d) C₁ -C₆ alkyl substituted with an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; or R^(5a) and R^(5b) are combined to form --(CH₂)_(s) --wherein one of the carbon atoms is optionally replaced by a moietyselected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--; R⁶ isindependently selected from hydrogen or C₁ -C₆ alkyl; R⁸ isindependently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl,alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; R¹² isa) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine, wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from: 1) C₁-C₆ alkyl, 2) aryl, 3) heterocycle, 4) --N(R¹¹)₂, 5) --OR¹⁰, or b)##STR39## R¹³ is independently selected from hydrogen and C₁ -C₆ alkyl;R¹⁴ is independently selected from C₁ -C₆ alkyl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ; Q is a substituted or unsubstitutednitrogen-containing C₆ -C₉ bicyclic ring system, wherein thenon-nitrogen containing ring is selected from an aromatic ring and aheterocycle; V is selected from:a) hydrogen, b) heterocycle, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,providedthat V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ isa bond, n is 0 and A² is S(O)_(m) ; W is a heterocycle; X, Y and Z areindependently H₂ or O;m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4or 5; t is 3, 4 or 5; and u is 0 or 1;or a pharmaceutically acceptablesalt thereof.
 3. A compound which inhibits Ras farnesyl-transferasehaving the Formula III: ##STR40## wherein: R^(1a) and R^(1b) areindependently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocyclic, cycloalkyl, alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --; R² and R³ are independently selectedfrom:a) a side chain of a naturally occurring amino acid, b) an oxidizedform of a side chain of a naturally occurring amino acid which is:i)methionine sulfoxide, or ii) methionine sulfone, and c) substituted orunsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group,wherein the substituent is selected from F, Cl,Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with an unsubstitutedor substituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; or R² and R³ are combined to form --(CH₂)_(s) --; or R² orR³ are combined with R⁶ to form a ring such that ##STR41## R^(4a),R^(4b), R^(7a) and R^(7b) are independently selected from: a)hydrogen,b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) aryl,heterocycle, cycloalkyl, alkenyl, R¹⁰ 0--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R⁶ is independently selected from hydrogen or C₁ -C₆alkyl; R⁸ is independently selected from:a) hydrogen, b) aryl,heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br,R¹⁰ 0--, R¹¹ S(O)m--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl,alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂,or R¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byperfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; A¹ and A² are independently selected from: a bond,--CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O,--N(R¹⁰)--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ; Q is asubstituted or unsubstituted nitrogen-containing C₆ -C₉ bicyclic ringsystem, wherein the non-nitrogen containing ring is selected from anaromatic ring and a heterocycle; V is selected from:a) hydrogen, b)heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atomsare replaced with a a heteroatom selected from O, S, and N, and e) C₂-C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m) and V isnot hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is aheterocycle; X, Y and Z are independently H₂ or O;m is 0, 1 or 2; n is0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5,provided that r is 0 when V is hydrogen; s is 4 or 5; t is 3, 4 or 5;and u is 0 or 1;or a pharmaceutically acceptable salt thereof.
 4. Aprodrug of the compound according to claim 3 illustrated by the formulaIV: ##STR42## wherein: R^(1a) and R^(1b) are independently selectedfrom:a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl,alkenyl, alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--; R² and R³ are independently selected from:a) a side chain of anaturally occurring amino acid, b) an oxidized form of a side chain of anaturally occurring amino acid which is:i) methionine sulfoxide, or ii)methionine sulfone, and c) substituted or unsubstituted C₁ -C₂₀ alkyl,C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclic group,whereinthe substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁-C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R² and R³ arecombined to form --(CH₂)_(s) --; or R² or R³ are combined with R⁶ toform a ring such that ##STR43## R^(4a), R^(4b), R^(7a) and R^(7b) areindependently selected from: a) hydrogen,b) C₁ -C₆ alkyl unsubstitutedor substituted by alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R⁶ is independently selectedfrom hydrogen or C₁ -C₆ alkyl; R⁸ is independently selected from:a)hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted byaryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--; R⁹ is selectedfrom:a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ isindependently selected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ; Q is a substituted or unsubstitutednitrogen-containing C₆ -C₉ bicyclic ring system, wherein thenon-nitrogen containing ring is selected from an aromatic ring and aheterocycle; V is selected from:a) hydrogen, b) heterocycle, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,providedthat V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ isa bond, n is 0 and A² is S(O)_(m) ; W is a heterocycle; X, Y and Z areindependently H₂ or O;n is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V ishydrogen; s is 4 or 5; t is 3, 4 or 5; and u is 0 or 1;or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 1 of the formula I: ##STR44## wherein: R^(1a) is independentlyselected from: hydrogen or C₁ -C₆ alkyl;R^(1b) is independently selectedfrom:a) hydrogen, b) aryl, heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂or alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, cycloalkyl, alkenyl, R¹⁰ 0--, or--N(R¹⁰)₂ ; R² and R³ areindependently selected from:a) a side chain of a naturally occurringamino acid, b) an oxidized form of a side chain of a naturally occurringamino acid which is:i) methionine sulfoxide, or ii) methionine sulfone,c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,wherein the substituent isselected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; or R² and R³ are combined to form --(CH₂)_(s) --; orR² or R³ are combined with R⁶ to form a ring such that ##STR45## R^(4a)and R^(7a) are independently selected from: a) hydrogen,b) C₁ -C₆ alkylunsubstituted or substituted by alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with an unsubstituted orsubstituted group selected from aryl, heterocyclic and C₃ -C₁₀cycloalkyl; R^(4b) and R^(7b) are hydrogen; R^(5a) is selected from:a) aside chain of a naturally occurring amino acid, wherein the amino acidis selected from methionine and glutamine, b) an oxidized form of a sidechain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, and c) substituted orunsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group,wherein the substituent is selected from F, Cl,Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; R^(5b) is selected from:a) hydrogen, and b) C₁ -C₃alkyl; R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl; R⁸ isindependently selected from:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R⁹ is selectedfrom:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; Q is selected from: ##STR46## A¹ and A² are independently selectedfrom: a bond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O,--N(R¹⁰)--, or S(O)_(m) ; V is selected from:a) hydrogen, b) heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; X, Y and Z areindependently H₂ or O;m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen; t is 3,4 or 5; and u is 0 or 1;or a pharmaceutically acceptable salt thereof.6. The compound according to claim 2 of the formula II: ##STR47##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl, c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl,R¹⁰ O--, or --N(R¹⁰)₂ ; R² and R³ are independently selected from:a) aside chain of a naturally occurring amino acid, b) an oxidized form of aside chain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C₁-C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclicgroup,wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, and d) C₁-C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R² and R³ arecombined to form --(CH₂)_(s) --; or R² or R³ are combined with R⁶ toform a ring such that ##STR48## R^(4a) and R^(7a) are independentlyselected from: a) hydrogen,b) C₁ -C₆ alkyl unsubstituted or substitutedby alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R^(4b) and R^(7b) are hydrogen; R^(5a) is selectedfrom:a) a side chain of a naturally occurring amino acid, wherein theamino acid is selected from methionine and glutamine, b) an oxidizedform of a side chain of a naturally occurring amino acid which is:i)methionine sulfoxide, or ii) methionine sulfone, and c) substituted orunsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group,wherein the substituent is selected from F, Cl,Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; R^(5b) is selected from:a) hydrogen, and b) C₁ -C₃alkyl; R⁶ is independently selected from hydrogen or C₁ -C₆ alkyl; R⁸ isindependently selected from:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰ --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R⁹ is selectedfrom:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,benzyl and aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; R¹² isa) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine, wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from:1) C₁-C₆ alkyl, 2) aryl, 3) heterocycle, 4) --N(R¹¹)₂, 5) --OR¹⁰, or b)##STR49## R¹³ is independently selected from hydrogen and C₁ -C₆ alkyl;R¹⁴ is independently selected from C₁ -C₆ alkyl; Q is selected from:##STR50## A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V isselected from:a) hydrogen, b) heterocycle selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C₁ -C₂₀ alkylwherein from 0 to 4 carbon atoms are replaced with a a heteroatomselected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V isnot hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, nis 0 and A² is S(O)_(m) ; W is a heterocycle selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, or isoquinolinyl; X, Y and Z are independently H₂ or O;m is0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5,provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and u is 0 or1;or the pharmaceutically acceptable salts thereof.
 7. The compoundaccording to claim 3 of the formula III: ##STR51## wherein: R^(1a) isindependently selected from: hydrogen or C₁ -C₆ alkyl;R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl, c) C₁ -C₆ alkyl unsubstitutedor substituted by aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R² and R³ are independently selected from:a) a side chain ofa naturally occurring amino acid, b) an oxidized form of a side chain ofa naturally occurring amino acid which is:i) methionine sulfoxide, orii) methionine sulfone, c) substituted or unsubstituted C₁ -C₁₀ alkyl,C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclic group,whereinthe substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R² and R³ are combined toform --(CH₂)_(s) --; or R² or R³ are combined with R⁶ to form a ringsuch that ##STR52## R^(4a) and R^(7a) are independently selected from:a) hydrogen,b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) aryl,heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R^(4b) and R^(7b) are hydrogen; R⁶ is independentlyselected from hydrogen or C₁ -C₆ alkyl; R⁸ is independently selectedfrom:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, RK¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; Q is selected from: ##STR53## A¹ and A² areindependently selected from: a bond, --CH═CH--, --C.tbd.C--, --C(O)--,--C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl,pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to4 carbon atoms are replaced with a a heteroatom selected from O, S, andN, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ isS(O)_(m) and V is not hydrogen if A¹ is a bond, n is 0 and A² isS(O)_(m) ; W is a heterocycle selected from pyrrolidinyl, imidazolyl,pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,or isoquinolinyl; X, Y and Z are independently H₂ or O;m is 0, 1 or 2; nis 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; r is 0 to 5,provided that r is 0 when V is hydrogen; t is 3, 4 or 5; and u is 0 or1;or a pharmaceutically acceptable salt thereof.
 8. The compoundaccording to claim 4 of the formula Formula IV: ##STR54## wherein:R^(1a) is independently selected from: hydrogen or C₁ -C₆ alkyl;R^(1b)is independently selected from:a) hydrogen, b) aryl, heterocycle,cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl, c) C₁ -C₆ alkyl unsubstitutedor substituted by aryl, heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R² and R³ are independently selected from:a) a side chain ofa naturally occurring amino acid, b) an oxidized form of a side chain ofa naturally occurring amino acid which is:i) methionine sulfoxide, orii) methionine sulfone, c) substituted or unsubstituted C₁ -C₁₀ alkyl,C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclic group,whereinthe substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R² and R³ are combined toform --(CH₂)_(s) --; or R² or R³ are combined with R⁶ to form a ringsuch that ##STR55## R^(4a) and R^(7a) are independently selected from:a) hydrogen,b) C₁ -C₆ alkyl unsubstituted or substituted by alkenyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) aryl,heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R^(4b) and R^(7b) are hydrogen; R⁶ is independentlyselected from hydrogen or C₁ -C₆ alkyl; R⁸ is independently selectedfrom:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OCO(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C.sub. 1-C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--,R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂-C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkylunsubstituted or substituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independentlyselected from hydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ isindependently selected from C₁ -C₆ alkyl and aryl; Q is selected from:##STR56## A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V isselected from:a) hydrogen, b) heterocycle selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C₁ -C₂₀ alkylwherein from 0 to 4 carbon atoms are replaced with a a heteroatomselected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V isnot hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond, nis 0 and A² is S(O)_(m) ; W is a heterocycle selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, or isoquinolinyl; X, Y and Z are independently H₂ or O;m is0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2; ris 0 to 5, provided that r is 0 when V is hydrogen; t is 3, 4 or 5; andu is 0 or 1;or a pharmaceutically acceptable salt thereof.
 9. A compoundwhich inhibits farnesyl-protein transferase whichis:N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl esterN-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionineN-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl esterN-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionineN-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl esterN-[(1H-imidazol-4-ylpropionyl)-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionineN-[(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionine methyl esterN-[(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)-amino-3(S)methylpentyl]-1,2,34-tetrahydro-3(S)-isoquinolinecarbonylmethionineN-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methioninemethyl ester orN-[N-(4-cyanobenzyl)-L-pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionineora pharmaceutically acceptable salt or optical isomer thereof.
 10. Thecompound according to claim 5 which inhibits farnesyl-proteintransferase whichis:N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine##STR57## or a pharmaceutically acceptable salt or optical isomerthereof.
 11. The compound according to claim 5 which inhibitsfarnesyl-protein transferase whichis:N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-(S)-isoquinolinecarbonyl-methioninemethyl ester ##STR58## or a pharmaceutically acceptable salt or opticalisomer thereof.
 12. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 2. 13. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 4. 14. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 9. 15. A method for inhibiting farnesylation of Ras protein whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of the composition of claim
 12. 16. A method forinhibiting farnesylation of Ras protein which comprises administering toa mammal in need thereof a therapeutically effective amount of thecomposition of claim
 13. 17. A method for inhibiting farnesylation ofRas protein which comprises administering to a mammal in need thereof atherapeutically effective amount of the composition of claim
 14. 18. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 12. 19. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim
 13. 20. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 14. 21. A method for treatingneurofibromin benign proliferative disorder which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 12. 22. A method for treating blindnessrelated to retinal vascularization which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 12. 23. A method for treating infections fromhepatitis delta and related viruses which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 12. 24. A method for preventing restenosis whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 12. 25. A method for treatingpolycystic kidney disease which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim 12.